Elucidating cutaneous mechanosensory circuits, from development to disease

摘要 触觉使我们能够感知物理世界并做出反应——我们识别物体 握在我们手中，区分不同的纹理和形状以及感觉运动 反馈电路协调我们的身体运动。触觉也是各种形式的基础 社会交换因此是人类经验的重要组成部分。第一步 导致触觉感知的是一组称为低感觉神经元的激活 阈值机械感受器 (LTMR)。有多种 LTMR 类型，每种类型都有其独特的特性 敏感性、形态、生理特性以及可能的功能。了解 每种 LTMR 类型的独特功能，以及 LTMR 活动的整体如何集成和 在中枢神经系统中处理形成触觉感知是该领域的悬而未决的问题。因此， 我的实验室的总体目标以及 R35 提案是：1）阐明敏感性， 哺乳动物皮肤主要类别的兴奋机制和独特功能 LTMR； 2）定义脊髓和脑干中LTMR电路组织的逻辑，以及 通往大脑的上行通路的本质是辨别性和情感性触摸的基础 感知； 3）建立外周体感系统在 发展； 4) 判断触摸电路及其功能是否以及如何出现故障 发育是自闭症谱系障碍和神经性疼痛期间触觉缺陷的基础。 我们正在使用一系列强大的小鼠分子遗传工具来实现这些目标，结合 具有复杂的电生理学、解剖学、行为和发育测定。 R35目标的成功完成将揭示体感神经的机制 系统开发与功能、脊髓触觉信息处理底层 正常和疾病条件下的感知。

Abstract The sense of touch allows us to perceive and respond to the physical world –we recognize objects held in our hands, discriminate between different textures and shapes, and sensory-motor feedback circuits coordinate our body movements. The sense of touch also underlies forms of social exchange and is thus an essential component of the human experience. The first step leading to touch perception is activation of a group of cutaneous sensory neurons called low- threshold mechanoreceptors (LTMRs). There are several LTMR types, and each has a unique sensitivity, morphology, physiological property and, presumably, function. Understanding the unique functions of each LTMR type, and how ensembles of LTMR activities are integrated and processed in the CNS to form touch percepts are outstanding questions in the field. Therefore, the overall goals of my laboratory, and thus this R35 proposal, are: 1) to elucidate the sensitivities, mechanisms of excitation, and unique functions of the major classes of mammalian cutaneous LTMRs; 2) to define the logic of LTMR circuit organization in the spinal cord and brainstem, and the nature of ascending pathways to the brain that underlie discriminative and affective touch perception; 3) to establish how the peripheral somatosensory system assembles during development; and 4) to determine whether and how dysfunction of touch circuits and their development underlies tactile deficits in autism spectrum disorders and during neuropathic pain. We are achieving these goals using an array of powerful mouse molecular genetic tools, combined with sophisticated electrophysiological, anatomical, behavioral and developmental assays. Successful completion of this R35's goals will thus reveal mechanisms of somatosensory nervous system development and function, and spinal cord touch information processing underlying perception, under normal and disease conditions.